Diversity Supplement to Fate, Function and Genetic Engineering of Breast Milk Cells for Infant Therapy

用于婴儿治疗的母乳细胞命运、功能和基因工程的多样性补充

• 批准号: 10406083
• 负责人: Kathryn A. Whitehead
• 金额: $ 9.49万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406083
• 关键词: Address; Animal Model; Antigens; Biodistribution; CAR T cell therapy; Cell Therapy; Cells; Consumption; DNA; Disease; Drug Delivery Systems; Epithelial Cells; FDA approved; Follow-Up Studies; Genetic Engineering; Human Milk; Immune; Immunotherapy; Infant; Location; Methods; Microfluidics; Milk; Mus; Nature; Neonatal; Output; Peptides; Pharmacotherapy; Procedures; Production; Proteins; RNA; System; Testing; Therapeutic; Time; Transfection; Vaccination; Viral; Vision; Work; base; cell behavior; cell type; effective therapy; milk expression; neonate; prevent; stem cell therapy; stem cells; success; transcription factor; uptake

PROJECT SUMMARY Each year, 15,000 infants die in the U.S. from diseases for which there are no effective therapies, and many more suffer through invasive procedures to address the diseases that are treatable. Here, we propose a non-invasive therapy based on the genetic engineering of breast milk cells to enable unprecedented production and delivery of therapeutics in infants. The approach is similar to the recently FDA-approved CAR-T therapy, except simpler, less invasive, and with broader potential use. Ultimately, we envision that cells will be isolated from freshly expressed milk, sorted by type, and transfected with RNA or DNA. Cells will then be reincorporated into milk for consumption. Each breast milk cell type has the potential for unique therapeutic functions: epithelial cells can operate as protein replacement “factories”, immune cells can produce peptide antigens for vaccination or immunotherapy, and stem cells can be programmed through the expression of transcription factors for cell therapy. This proposal will take the first, most important steps in achieving our long-term therapeutic vision. First, we will establish a basic understanding of breast milk cell subsets, their biodistribution in mouse neonates, and their transport mechanisms. We will determine if breast milk cell uptake is facilitated by cell attributes, other milk components, and/or the nature of the neonatal gut. We will also establish breast milk cell persistence times in the neonate as a function of location. Several transfection methods, including viral, non-viral, and microfluidic systems will be tested for their ability to maximize protein output without compromising cell transport. Finally, we will pursue therapeutic applications informed by our fundamental studies, including protein replacement, vaccination, immunotherapy, and stem cell therapy. Initial successes will set the stage for follow-up studies in animal models of neonatal disease and the eventual non-invasive treatment of infants for whom there are no currently available therapies.

项目摘要 在美国，每年有15，000名婴儿死于没有有效治疗方法的疾病。 治疗，还有更多的人通过侵入性程序来解决这些疾病， 可以治疗的在这里，我们提出了一种基于母乳基因工程的非侵入性疗法 细胞，使前所未有的生产和婴儿治疗交付。该方法是 类似于最近FDA批准的CAR-T疗法，除了更简单，侵入性更小， 潜在用途。最终，我们设想细胞将从新鲜挤出的乳汁中分离出来， 型，并用RNA或DNA转染。然后，细胞将重新融入牛奶中供消费。 每一种母乳细胞类型都有独特的治疗功能：上皮细胞可以 作为蛋白质替代"工厂"，免疫细胞可以产生用于疫苗接种的肽抗原， 干细胞可以通过转录因子的表达进行编程， 细胞疗法 这项提案将采取第一个，最重要的步骤，在实现我们的长期治疗， 视野首先，我们将建立一个基本的了解母乳细胞亚群，它们的生物分布在 小鼠新生儿及其转运机制。我们将确定母乳细胞的摄取是否 通过细胞属性、其他乳成分和/或新生儿肠道的性质来促进。我们还将 建立母乳细胞在新生儿中的持续时间作为位置的函数。多次转染 包括病毒、非病毒和微流控系统在内的方法将被测试其最大化 蛋白质输出而不影响细胞运输。最后，我们将追求治疗应用 通过我们的基础研究，包括蛋白质替代，疫苗接种，免疫治疗， 干细胞治疗初步的成功将为新生儿动物模型的后续研究奠定基础。 疾病和最终的非侵入性治疗的婴儿谁没有目前可用 治疗

项目成果

The Effect of Infant Gastric Digestion on Human Maternal Milk Cells.

• DOI: 10.1002/mnfr.202200090
• 发表时间: 2022-10
• 期刊: Molecular nutrition & food research
• 影响因子: 5.2

The replacement of helper lipids with charged alternatives in lipid nanoparticles facilitates targeted mRNA delivery to the spleen and lungs.

• DOI: 10.1016/j.jconrel.2022.03.046
• 发表时间: 2022-05
• 期刊: JOURNAL OF CONTROLLED RELEASE
• 影响因子: 10.8
• 作者: LoPresti, Samuel T.;Arral, Mariah L.;Chaudhary, Namit;Whitehead, Kathryn A.
• 通讯作者: Whitehead, Kathryn A.

The strawberry-derived permeation enhancer pelargonidin enables oral protein delivery.

• DOI: 10.1073/pnas.2207829119
• 发表时间: 2022-08-16
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1

The mixing method used to formulate lipid nanoparticles affects mRNA delivery efficacy and organ tropism.

• DOI: 10.1016/j.ejpb.2023.10.006
• 发表时间: 2023-10
• 期刊: European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V
• 作者: Daria M. Strelkova Petersen;Namit Chaudhary;Mariah L. Arral;Ryan M. Weiss;Kathryn A. Whitehead

The enhanced intestinal permeability of infant mice enables oral protein and macromolecular absorption without delivery technology.

• DOI: 10.1016/j.ijpharm.2020.120120
• 发表时间: 2021-01-25
• 期刊: International journal of pharmaceutics
• 影响因子: 5.8
• 作者: Gleeson JP;Fein KC;Chaudhary N;Doerfler R;Newby AN;Whitehead KA
• 通讯作者: Whitehead KA